Gabapentin is useful in treating epilepsy and various other cerebral disorders and is chemically 1-(amino methyl) cyclohexane acetic acid(I), having the structure shown below:

Gabapentin was first disclosed by Warner-Lambert Co. in U.S. Pat. No. 4,024,175. A process for the preparation of gabapentin is described in U.S. Pat. No. 4,087,544 (Scheme 1). It involves converting cyclohexane diacetic acid (CDA, II) to its anhydride(III) followed by treatment with ammonia to give 1, 1-cyclohexane diacetic acid monoamide (CDMA, IV). The CDMA (IV) is subjected to Hofmann reaction to obtain Gabapentin.

The required CDA (II) is prepared as described in U.S. Pat. No. 2,960,441 assigned to Warner-Lambert Co. The process involves Guareschi reaction between cyclohexanone and alkyl cyanoacetate in the presence of ammonia to obtain 2, 4-dioxo-3-aza-spiro [5.5] undecane-1, 5-dicarbonitrile (dinitrile, V) which on reaction with sulphuric acid undergoes hydrolysis and decarboxylation to give CDA (II, Scheme 2).

The process, especially the second step of converting dinitrile V to CDA (II), is very problematic. Firstly, the reaction requires the use of concentrated (95.6%) sulphuric acid and the reaction is carried out at 160° to 190° C. for several hours. During the decarboxylation reaction copious amount of carbon dioxide is liberated, resulting in frothing. The international patent application, WO 03/002504 also refers to the foaming problem faced during the decarboxylation step when carried out according to U.S. Pat. No. 2,960,441. The WO 03/002504 describes a slightly modified process involving two steps. In the first step, dinitrile V is reacted with 75 to 90% H2SO4 at 65° to 85° C. In the second step, the reaction mixture from the first step is reacted with 60 to 80% H2SO4 maintained at about 170° C. During the second step carbon dioxide liberation takes place. To avoid foaming, the addition is carried out slowly over a long period of time. But the process remains cumbersome, as it requires addition of a reaction mixture present in a 75-90% sulphuric acid solution to another sulphuric acid solution of 60-80% concentration at 170° C., while carbon dioxide gas is liberated.
Thorpe and Wood (J. Chem. Soc. 1913, 1586-1600) reported another method for the preparation of CDA (II) which involves reacting dinitrile V with sulphuric acid to obtain spiro[cyclohexane-1,9′-(3,7-diazabicyclo-[3.3.1]nonane)]-2′,4′,6′,8′-tetraone (diimide, VI), which on further acid hydrolysis gives CDA (II, Scheme 3). However, no experimental details were given for the reactions.

McElvain and Clemens (J. American Chemical Society, 1958, 80, 3915-3023) reported the synthesis of a number of related aromatic derivatives of diimides from the corresponding dinitriles and converting the diimides to corresponding diacids.
J. Med. Chem., 1998, 41, pg. 318-331, describes the preparation of diimide VI from dinitrile V by reacting with 60% sulphuric acid at a temperature of 120° to 140° C. for 10 to 15 minutes. However, the yield of the diimide VI obtained is only 40%. Earlier, U.S. Pat. No. 4,742,172 also reported the reaction under similar conditions.
Preparation of CDMA (IV) from dinitrile V, without going through CDA (II) as the intermediate, is reported in U.S. Pat. No. 7,759,517 (Scheme 4). Here, dinitrile is converted to diamide VII followed by sodium salt of diacid VIII. The diacid salt VIII is then converted to a monoimide IX followed by its hydrolysis to CDMA (IV).

Thus there is a need for a better process which is environmentally safe and can be applied at industrial scale in a cost effective manner.